CN113143886A - 一种氢溴酸伏硫西汀微丸缓释制剂的制备方法 - Google Patents
一种氢溴酸伏硫西汀微丸缓释制剂的制备方法 Download PDFInfo
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- CN113143886A CN113143886A CN202110493135.6A CN202110493135A CN113143886A CN 113143886 A CN113143886 A CN 113143886A CN 202110493135 A CN202110493135 A CN 202110493135A CN 113143886 A CN113143886 A CN 113143886A
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- vortioxetine hydrobromide
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- Medicinal Preparation (AREA)
Abstract
本发明公开了一种氢溴酸伏硫西汀微丸缓释制剂的制备方法,属于药物制剂领域。本发明的氢溴酸伏硫西汀微丸缓释制剂由如下重量百分比的原料制成:氢溴酸伏硫西汀9.5‑10.0%、水溶性分散载体35‑40%、填充剂15‑45%、骨架材料2.5‑3.5%、崩解剂2.0‑3.5%、缓释包衣材料6‑36%。本发明制备的氢溴酸伏硫西汀微丸缓释制剂可以改善忧郁症患者的服药顺应性,可延缓氢溴酸伏硫西汀体内释放,延长体内半衰期,改善药物在体内的药代动力学性质,避免过高血药浓度、降低药物的毒副反应,进而提高其生物利用度。
Description
技术领域
本发明涉及药物制剂技术领域,具体涉及一种氢溴酸伏硫西汀微丸缓释制剂的制备方法。
背景技术
我国抑郁人口近亿,占总人群的7.3%。其中抑郁障碍患者人数约0.55亿,患病率4.2%;焦虑障碍人数约为0.41亿,患病率3.1%。但目前我国抑郁症患者就诊率低,真正接受抗抑郁有效治疗的患者比例依然不足10%。
氢溴酸伏硫西汀(Vortioxetine)是用于治疗抑郁症的药物,其结构式如下:
伏硫西汀原料药有三种晶型,分别为:α、β、γ,根据FDA原研说明书描述,伏硫西汀片晶型为β晶型。灵北(Lundbeck)制药公司和武田(Takeda)公司于2012年12月向美国食品药品监督管理局(FDA,Food and DrugAdministration)提交新药申请(NDA,NewDrugApplication),于2013年9月30日获FDA正式批准(注册审批号:NDA204447);于2013年12月18日获欧洲药品管理局(EMA,European MedicinesAgency)批准,注册审批号:EMEA/H/C002717;于2017年11月21日获中国国家药品监督管理局(CFDA,China Food andDrugAdministration)批准,批准文号:H20170381、H20170382、H20170383、H20170384(4种剂量)。
在治疗抑郁症方面,氢溴酸伏硫西汀具有如下优势:
(1)耐受性好,副作用小:氢溴酸伏硫西汀反馈出来最大的副作用在胃肠消化道,会出现恶心等症状,但是一段时间后会慢慢稳定,副作用消失。
(2)停药反应小:传统的五羟色胺再摄取抑制剂(Selective Serotonin ReuptakeInhibitor,SSRI)需要逐级减量以实现状态稳定后的减量或停药,如果处理不当,骤停会带来更难受的停药副作用。氢溴酸伏硫西汀可以直接突然停药。
(3)改善认知:2015年8月,灵北和武田向FDA提交了补充新药申请,拟把氢溴酸伏硫西汀治疗重度抑郁症MDD(Major Depressive Disorder)某些认知功能的疗效数据添加到标签内容。而更早些时候,在欧洲,氢溴酸伏硫西汀获得了EMA旗下CHMP(Committee forMedicinal Products for Human Use,人用医药产品委员会)支持,获批成为欧盟首款用于改善抑郁症患者认知功能的抗抑郁症药物。
(4)主要经肝脏代谢:半衰期为66小时,要通过肝CYP450酶系代谢,主要为CYP2D6,其他包括CYP3A4、CYP3A5、CYP2C9及CYP2C19;不受肾功能影响。
目前上市的氢溴酸伏硫西汀制剂为普通常释放制剂,为5mg、10mg、20mg规格。但还未见有氢溴酸伏硫西汀缓释制剂的相关研究。
发明内容
针对上述现有技术,本发明的目的是提供一种氢溴酸伏硫西汀微丸缓释制剂的制备方法。本发明填补了氢溴酸伏硫西汀缓释制剂研究的空白。本发明制备的氢溴酸伏硫西汀微丸缓释制剂可以改善忧郁症患者的服药顺应性,可延缓氢溴酸伏硫西汀体内释放,延长体内半衰期,改善药物在体内的药代动力学性质,避免过高血药浓度、降低药物的毒副反应,进而提高其生物利用度。
为实现上述目的,本发明采用如下技术方案:
本发明的第一方面,提供一种氢溴酸伏硫西汀微丸缓释制剂,由如下重量百分比的原料制成:
氢溴酸伏硫西汀9.5-10.0%、水溶性分散载体35-40%、填充剂15-45%、骨架材料2.5-3.5%、崩解剂2.0-3.5%、缓释包衣材料6-36%。
优选的,所述氢溴酸伏硫西汀微丸缓释制剂,由如下重量百分比的原料制成:
氢溴酸伏硫西汀9.78%、水溶性分散载体36.17%、填充剂28.54%、骨架材料3.08%、崩解剂3.08%、缓释包衣材料19.35%。
优选的,所述水溶性分散载体为聚乙烯吡咯烷酮(PVP)、大豆磷脂、聚乙二醇(PEG)、泊洛沙姆(poloxamer)、甘露糖醇、木糖醇、枸橼酸、酒石酸中的一种或多种。
更优选的,所述水溶性分散载体为聚维酮K30和大豆磷脂。
优选的,所述骨架材料为羟丙甲纤维素、甲基纤维素、羟乙基纤维素、非纤维素类多糖、天然胶类、不溶性骨架材料、惰性脂肪或蜡类中的一种或多种。
优选的,所述填充剂为微晶纤维素、硅化微晶纤维素、淀粉、可压性淀粉、乳糖、糊精、糖粉、无机盐类、甘露醇中的一种或多种。
优选的,所述崩解剂为交联羧甲基纤维素钠、干淀粉、羧甲基淀粉钠中的一种或多种。
优选的,所述缓释包衣材料由主缓释材料、增塑剂和抗黏剂按重量比(5-27):(0.5-5):(0.5-2)组成;
所述主缓释材料为乙基纤维素、醋酸纤维素、丙烯酸树脂类中的一种或多种;
所述增塑剂为PEG 4000;
所述抗黏剂为滑石粉、硬脂酸镁、SDS、微粉硅胶、氢化植物油、蜡质类、邻苯二甲酸酯类中的一种或多种。
本发明的第二方面,提供上述氢溴酸伏硫西汀微丸缓释制剂的制备方法,包括以下步骤:
(1)将氢溴酸伏硫西汀和水溶性分散载体溶解于无水乙醇中,于40~60℃的条件下水浴旋转蒸发至液体呈粘稠状,然后在60~80℃的条件下完全挥干溶剂,-20℃放置4h,干燥,取出,粉碎,过40~80目筛,制备得到固体分散体;
(2)将步骤(1)制备的固体分散体与填充剂、骨架材料和崩解剂混合,以水为润湿剂,挤出滚圆制备氢溴酸伏硫西汀骨架微丸;
(3)将缓释包衣材料溶于无水乙醇中,配制成缓释包衣液;利用缓释包衣液对步骤(2)制备的氢溴酸伏硫西汀骨架微丸进行包衣处理,制备得到氢溴酸伏硫西汀微丸缓释制剂。
优选的,步骤(2)中,挤出滚圆制备氢溴酸伏硫西汀骨架微丸的具体条件为:挤出转速为1000rpm,滚圆转速为1500rpm,进风速度30Hz,出风速度26Hz,进风温度为50℃,物料温度为45℃。
优选的,步骤(3)中,包衣处理的具体条件为:包衣转速为900rpm,进风速度30Hz,出风速度26Hz,包衣喷枪喷雾速度为1mL·min-1,进风温度为45℃,物料温度为38℃,包衣2-3h。
本发明的有益效果:
本发明采用先制备固体分散体,再制备骨架微丸,并通过缓释包衣控制释放的方法制备氢溴酸伏硫西汀骨架缓释微丸制剂,实现了氢溴酸伏硫西汀先增溶后缓释的目的。本方法实验操作简单,具有良好的应用前景,为氢溴酸伏硫西汀的深度利用提供了一种思路与策略。
体外实验结果显示,氢溴酸伏硫西汀固体分散体能起到明显的增溶作用,释放迅速,在不同介质中均能极短时间内释放,1h内释放度均在85%以上;氢溴酸伏硫西汀骨架缓释微丸在不同溶出介质中均显示出良好的缓释效果,24h内在不同溶出介质中释放均达到90%以上。
附图说明
图1:氢溴酸伏硫西汀原料药、本发明制备的固体分散体溶出曲线(pH1.0)。
图2:本发明制备的氢溴酸伏硫西汀微丸缓释制剂的溶出曲线(pH1.0、4.5、6.8、水)。
具体实施方式
应该指出,以下详细说明都是例示性的,旨在对本申请提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
正如背景技术部分介绍的,现有的氢溴酸伏硫西汀均为普通常释放制剂。因此,口服固体骨架缓释制剂的研究就十分有意义,可填补相应氢溴酸伏硫西汀制剂研究的空白。氢溴酸伏硫西汀骨架缓释制剂可以改善忧郁症患者的服药顺应性,可延缓氢溴酸伏硫西汀体内释放,延长体内半衰期,改善药物在体内的药代动力学性质,避免过高血药浓度、降低药物的毒副反应,进而提高其生物利用度。
为开发氢溴酸伏硫西汀的缓释制剂,本发明的设计思路为:基于氢溴酸伏硫西汀难溶于水的特点,本发明采用先制备固体分散体,再制备骨架微丸,并通过缓释包衣控制释放的方法制备氢溴酸伏硫西汀骨架缓释微丸制剂,实现了氢溴酸伏硫西汀先增溶后缓释的目的。
伏硫西汀是低溶解度药物,单纯药物制备缓释微丸,无法解决体内溶解较低的问题,因此,首要问题是增加药物的溶解度,本发明通过固体分散体技术,制备含药固体分散体,并在体外论证其增溶作用,可达到迅速释放(图1),再以此固体分散体制备缓释骨架微丸,控制药物的实际释放,达到缓释的目的。针对药物体内溶解度低的问题,本发明将本来难溶的药物,通过增溶和缓释的双重作用,达到良好的药效。
本发明的氢溴酸伏硫西汀骨架缓释微丸制剂由三步制备而成:
步骤一:制备氢溴酸伏硫西汀固体分散体
将氢溴酸伏硫西汀和水溶性分散载体溶解于无水乙醇中,于40~60℃的条件下水浴旋转蒸发至液体呈粘稠状,然后在60~80℃的条件下完全挥干溶剂,-20℃放置4h,干燥,取出,粉碎,过40~80目筛,制备得到固体分散体。
所述水溶性分散载体包括但不限于聚乙二醇(PEG)类、聚乙烯吡咯烷酮(PVP)、大豆磷脂、泊洛沙姆(poloxamer)、甘露糖醇、木糖醇、枸橼酸、酒石酸等。
步骤二:以氢溴酸伏硫西汀固体分散体为材料,挤出滚圆制备氢溴酸伏硫西汀骨架微丸
将制备的固体分散体与填充剂、骨架材料和崩解剂混合,以水为润湿剂,挤出滚圆制备氢溴酸伏硫西汀骨架微丸。
骨架材料包括但不限于:羟丙甲纤维素(如K100、K4M、K15M等)、其他纤维素衍生物(如甲基纤维素、羟乙基纤维素、羟甲基纤维素钠等)、非纤维素类多糖(如壳聚糖等)、天然胶类(果胶、阿拉伯胶海藻酸钠等)、不溶性骨架材料(如乙基纤维素、聚乙烯、聚氧乙烯等)、惰性脂肪或蜡类(如蜂蜡、氢化植物油、巴西棕榈蜡、甘油硬脂酸酯、丙二醇硬脂酸酯等)。
步骤三:以氢溴酸伏硫西汀骨架微丸为材料,通过流化床法包衣缓释层,制备得到氢溴酸伏硫西汀骨架缓释微丸制剂。
将缓释包衣材料溶于无水乙醇中,配制成缓释包衣液;利用缓释包衣液对制备的氢溴酸伏硫西汀骨架微丸进行包衣处理,制备得到氢溴酸伏硫西汀微丸缓释制剂。
等)或以上所述不同型号的不同比例的混合缓释薄膜包衣材料。
为了使得本领域技术人员能够更加清楚地了解本申请的技术方案,以下将结合具体的实施例详细说明本申请的技术方案。
本发明实施例中所用的未进行具体说明试验材料均为本领域常规的试验材料,均可通过商业渠道购买得到。
实施例1:
处方信息如下:
(1)氢溴酸伏硫西汀、PVPK90与泊洛沙姆188依次按处方量溶解于80mL体积浓度为50%乙醇溶液中,于60℃的条件下水浴旋转蒸发至液体呈粘稠状,在80℃的条件下完全挥干溶剂,-20℃冰箱放置4h,其后于真空干燥箱内50℃条件下烘24h,取出,粉碎,过60目筛,存放与干燥器内备用。
(2)骨架缓释微丸制备时按处方量称取固体分散体、羟丙甲纤维素K100、交联羧甲基纤维素钠以及硅化微晶纤维素,以水为润湿剂,经过充分搅拌混合后,调节相关仪器参数:挤出转速为1000rpm,滚圆转速为1500rpm,进风速度30Hz,出风速度26Hz,进风温度为50℃,物料温度为45℃。挤出滚圆制备氢溴酸伏硫西汀骨架微丸,制备得的骨架微丸于真空干燥箱内50℃条件下烘4h,取出后存放与干燥器内备用。
(3)取上述制备的氢溴酸伏硫西汀骨架微丸,置于流化床中,恒温流化预热30min。精密称取处方量的缓释材料及其他药用辅料共溶于无水乙醇中,配制成缓释包衣液,磁力搅拌1.5h,待包衣液均匀后,调节相关仪器参数:包衣转速为900rpm,进风速度30Hz,出风速度26Hz,包衣喷枪喷雾速度为1mL·min-1,进风温度为45℃,物料温度为38℃,包衣4h,包衣结束后取出微丸,放入烘箱50℃干燥6h,即得氢溴酸伏硫西汀骨架缓释微丸制剂。
实施例2:
处方信息如下:
(1)氢溴酸伏硫西汀、PVP K30与大豆磷脂依次按处方量溶解于80mL无水乙醇中,于40℃的条件下水浴旋转蒸发至液体呈粘稠状,在80℃的条件下完全挥干溶剂,-20℃冰箱放置4h,其后于真空干燥箱内50℃条件下烘24h,取出,粉碎,过60目筛,存放与干燥器内备用。
(2)骨架缓释微丸制备时按处方量称取固体分散体、羟丙甲纤维素K100、交联羧甲基纤维素钠以及微晶纤维素,以水为润湿剂,经过充分搅拌混合后,调节相关仪器参数:挤出转速为1000rpm,滚圆转速为1500rpm,进风速度30Hz,出风速度26Hz,进风温度为50℃,物料温度为45℃。挤出滚圆制备氢溴酸伏硫西汀骨架微丸,制备得的骨架微丸于真空干燥箱内50℃条件下烘4h,取出后存放与干燥器内备用。
(3)取上述制备的氢溴酸伏硫西汀骨架微丸,置于流化床中,恒温流化预热30min。精密称取处方量的缓释材料及其他药用辅料共溶于无水乙醇中,配制成缓释包衣液,磁力搅拌1.5h,待包衣液均匀后,调节相关仪器参数:包衣转速为900rpm,进风速度30Hz,出风速度26Hz,包衣喷枪喷雾速度为1mL·min-1,进风温度为45℃,物料温度为38℃,包衣3h,包衣结束后取出微丸,放入烘箱50℃干燥6h,即得氢溴酸伏硫西汀骨架缓释微丸制剂。
试验例:溶出试验
国家颁布的《普通口服固体制剂溶出度试验技术指导原则》内对溶出介质有详细规定:体积一般为500、900或1000mL,溶出介质的体积最好能满足漏槽条件,一般应采用pH值1.2~6.8的水性介质。可采用不含酶的pH 1.2、6.8的溶出介质作为人工胃液和人工肠液。特殊情况下,可采用高pH的溶出介质,但一般不应超过pH 8.0。同时参照FDA规定,对本发明制备的氢溴酸伏硫西汀微丸缓释制剂进行溶出试验,本发明选择的介质为:pH1.0、pH4.5、pH6.8、水,搅拌方式为:桨法,转速为:50rpm,介质体积:900ml,取样点设置为:1h、2h、4h、6h、8h、10h、12h、16h、20h、24h。
其中,实施例1制备的氢溴酸伏硫西汀骨架缓释微丸制剂的溶出曲线如图2所示。结果表明,本发明制备的氢溴酸伏硫西汀微丸缓释制剂,工艺稳定,能很好起到缓释的作用,24h内的释放稳定,无突释和难以溶出的现象出现。
以上所述仅为本申请的优选实施例而已,并不用于限制本申请,对于本领域的技术人员来说,本申请可以有各种更改和变化。凡在本申请的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本申请的保护范围之内。
Claims (10)
1.一种氢溴酸伏硫西汀微丸缓释制剂,其特征在于,由如下重量百分比的原料制成:
氢溴酸伏硫西汀9.5-10.0%、水溶性分散载体35-40%、填充剂15-45%、骨架材料2.5-3.5%、崩解剂2.0-3.5%、缓释包衣材料6-36%。
2.根据权利要求1所述的氢溴酸伏硫西汀微丸缓释制剂,其特征在于,由如下重量百分比的原料制成:
氢溴酸伏硫西汀9.78%、水溶性分散载体36.17%、填充剂28.54%、骨架材料3.08%、崩解剂3.08%、缓释包衣材料19.35%。
3.根据权利要求1或2所述的氢溴酸伏硫西汀微丸缓释制剂,其特征在于,所述水溶性分散载体为聚乙烯吡咯烷酮、大豆磷脂、聚乙二醇、泊洛沙姆、甘露糖醇、木糖醇、枸橼酸、酒石酸中的一种或多种。
4.根据权利要求1或2所述的氢溴酸伏硫西汀微丸缓释制剂,其特征在于,所述骨架材料为羟丙甲纤维素、甲基纤维素、羟乙基纤维素、非纤维素类多糖、天然胶类、不溶性骨架材料、惰性脂肪或蜡类中的一种或多种。
5.根据权利要求1或2所述的氢溴酸伏硫西汀微丸缓释制剂,其特征在于,所述填充剂为微晶纤维素、硅化微晶纤维素、淀粉、可压性淀粉、乳糖、糊精、糖粉、无机盐类、甘露醇中的一种或多种。
6.根据权利要求1或2所述的氢溴酸伏硫西汀微丸缓释制剂,其特征在于,所述崩解剂为交联羧甲基纤维素钠、干淀粉、羧甲基淀粉钠中的一种或多种。
7.根据权利要求1或2所述的氢溴酸伏硫西汀微丸缓释制剂,其特征在于,所述缓释包衣材料由主缓释材料、增塑剂和抗黏剂按重量比(5-27):(0.5-5):(0.5-2)组成;
所述主缓释材料为乙基纤维素、醋酸纤维素、丙烯酸树脂类中的一种或多种;
所述增塑剂为PEG 4000;
所述抗黏剂为滑石粉、硬脂酸镁、SDS、微粉硅胶、氢化植物油、蜡质类、邻苯二甲酸酯类中的一种或多种。
8.权利要求1-7任一项所述的氢溴酸伏硫西汀微丸缓释制剂的制备方法,其特征在于,包括以下步骤:
(1)将氢溴酸伏硫西汀和水溶性分散载体溶解于无水乙醇中,于40~60℃的条件下水浴旋转蒸发至液体呈粘稠状,然后在60~80℃的条件下完全挥干溶剂,-20℃放置4h,干燥,取出,粉碎,过40~80目筛,制备得到固体分散体;
(2)将步骤(1)制备的固体分散体与填充剂、骨架材料和崩解剂混合,以水为润湿剂,挤出滚圆制备氢溴酸伏硫西汀骨架微丸;
(3)将缓释包衣材料溶于无水乙醇中,配制成缓释包衣液;利用缓释包衣液对步骤(2)制备的氢溴酸伏硫西汀骨架微丸进行包衣处理,制备得到氢溴酸伏硫西汀微丸缓释制剂。
9.根据权利要求8所述的制备方法,其特征在于,步骤(2)中,挤出滚圆制备氢溴酸伏硫西汀骨架微丸的具体条件为:挤出转速为1000rpm,滚圆转速为1500rpm,进风速度30Hz,出风速度26Hz,进风温度为50℃,物料温度为45℃。
10.根据权利要求8所述的制备方法,其特征在于,步骤(3)中,包衣处理的具体条件为:包衣转速为900rpm,进风速度30Hz,出风速度26Hz,包衣喷枪喷雾速度为1mL·min-1,进风温度为45℃,物料温度为38℃,包衣2-3h。
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1923166A (zh) * | 2006-09-07 | 2007-03-07 | 何岩 | 卡维地洛控释制剂 |
CN104224732A (zh) * | 2014-09-29 | 2014-12-24 | 江苏大学 | 一种口服骨架型环孢素a缓释微丸制剂及其制备方法 |
WO2016062860A1 (en) * | 2014-10-24 | 2016-04-28 | H E X A L Aktiengesellschaft | Amorphous vortioxetine hydrobromide |
US20160214949A1 (en) * | 2013-09-30 | 2016-07-28 | Cadila Healthcare Limited | An amorphous vortioxetine and salts thereof |
WO2016116077A1 (en) * | 2015-01-21 | 2016-07-28 | Zentiva, K.S. | Polymer-stabilized amorphous forms of vortioxetine |
CN106727438A (zh) * | 2017-02-23 | 2017-05-31 | 佛山市弘泰药物研发有限公司 | 一种沃替西汀缓释胶囊及其制备方法 |
CN110787144A (zh) * | 2018-08-03 | 2020-02-14 | 南京济群医药科技股份有限公司 | 一种含有氢溴酸伏硫西汀的薄膜包衣片及其制备方法 |
CN110812342A (zh) * | 2018-08-10 | 2020-02-21 | 郑州泰丰制药有限公司 | 一种盐酸帕罗西汀肠溶缓释微丸的制备方法 |
CN110934853A (zh) * | 2019-12-30 | 2020-03-31 | 鲁南制药集团股份有限公司 | 一种枸橼酸莫沙必利缓释微丸胶囊及其制备方法 |
-
2021
- 2021-05-07 CN CN202110493135.6A patent/CN113143886A/zh active Pending
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1923166A (zh) * | 2006-09-07 | 2007-03-07 | 何岩 | 卡维地洛控释制剂 |
US20160214949A1 (en) * | 2013-09-30 | 2016-07-28 | Cadila Healthcare Limited | An amorphous vortioxetine and salts thereof |
CN104224732A (zh) * | 2014-09-29 | 2014-12-24 | 江苏大学 | 一种口服骨架型环孢素a缓释微丸制剂及其制备方法 |
WO2016062860A1 (en) * | 2014-10-24 | 2016-04-28 | H E X A L Aktiengesellschaft | Amorphous vortioxetine hydrobromide |
US20170333424A1 (en) * | 2014-10-24 | 2017-11-23 | Hexal Ag | Amorphous Vortioxetine Hydrobromide |
WO2016116077A1 (en) * | 2015-01-21 | 2016-07-28 | Zentiva, K.S. | Polymer-stabilized amorphous forms of vortioxetine |
CN106727438A (zh) * | 2017-02-23 | 2017-05-31 | 佛山市弘泰药物研发有限公司 | 一种沃替西汀缓释胶囊及其制备方法 |
CN110787144A (zh) * | 2018-08-03 | 2020-02-14 | 南京济群医药科技股份有限公司 | 一种含有氢溴酸伏硫西汀的薄膜包衣片及其制备方法 |
CN110812342A (zh) * | 2018-08-10 | 2020-02-21 | 郑州泰丰制药有限公司 | 一种盐酸帕罗西汀肠溶缓释微丸的制备方法 |
CN110934853A (zh) * | 2019-12-30 | 2020-03-31 | 鲁南制药集团股份有限公司 | 一种枸橼酸莫沙必利缓释微丸胶囊及其制备方法 |
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